Angewandte

Chemie

DOI: 10.1002/anie.201402573

Trifluoromethylthiolation

Silver-Catalyzed Decarboxylative Trifluoromethylthiolation of Aliphatic Carboxylic Acids in Aqueous Emulsion** Feng Hu, Xinxin Shao, Dianhu Zhu, Long Lu, and Qilong Shen* Abstract: A silver-catalyzed decarboxylative trifluoromethylthiolation of secondary and tertiary carboxylic acids under mild conditions tolerates a wide range of functional groups. The reaction was dramatically accelerated by its performance in an aqueous emulsion, which was formed by the addition of sodium dodecyl sulfate to water. It was proposed that the radical, which was generated from the silver-catalyzed decarboxylation in the “oil-in-water” droplets, could easily react with the trifluoromethylthiolating reagent to form the product.

As the most electronegative element, fluorine has played a pivotal role in agrochemistry and pharmaceutical chemistry, with an increasing number of fluorinated drugs on the market and drug candidates under development at different stages.[1] Among the different fluorinated functional groups, the trifluoromethylthio group (CF3S) is highly valuable because of its advantageous effects, as the incorporation of the trifluoromethylthio group often improves the lipophilicity of a compound and suppresses metabolic detoxification processes to increase the in vivo lifetime of a drug.[2] This fact has stimulated a growing interest in the development of new reagents and methods for the direct introduction of the trifluoromethylthio group under mild conditions.[3] For instance, several electrophilic trifluoromethylthiolating reagents have been developed, which allow the trifluoromethylthiolation of common nucleophiles, such as b-ketoesters, alkynes, aryl or alkyl Grignard reagents, and lithium reagents.[4, 5a–j] In addition, significant advances have been achieved recently in the transition-metal-mediated trifluoromethylthiolation, with functional groups such as aryl boronic acids and halides undergoing efficient trifluoromethylthiolation under palladium, nickel, or copper catalysis.[5k–p] Despite these recent great achievements in this area, methods for the general and site-specific formation of sp3hybridized secondary or tertiary carbon SCF3 bonds are [*] Dr. F. Hu,[+] X. Shao,[+] D.-H. Zhu, Prof. Dr. L. Lu, Prof. Dr. Q. Shen Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences 345 Lingling Road, Shanghai 200032 (China) E-mail: [email protected]

limited.[7, 8] Billard and co-workers reported the electrophilic addition of a trifluoromethylthiolated reagent to olefins in excellent yields.[5b] Qing and co-workers reported reactions of allylsilane or tryptamine derivatives with Billards reagent to form secondary or tertiary alkyl trifluoromethylthioethers.[5d,f] The groups of Shen and Shibata independently reported the trifluoromethylthiolation of b-ketoesters with two different electrophilic trifluoromethylthiolating reagents.[6a,b, 5i] More recently, the groups of Rueping and Shen reported the asymmetric trifluoromethylthiolation of b-ketoesters.[5j, 6b] Reactions using Billards reagent generally required the use of a strong Lewis or Brønsted acid to activate the CF3S reagent. Other reactions only proceeded in high yields with asubstituted b-ketoesters. Thus, the development of new methods for the direct introduction of the trifluoromethylthio group at sp3-hybridized secondary or tertiary carbon centers with broad substrate scope and functional-group tolerance is highly desirable. Aliphatic carboxylic acids are air- and water-stable, readily available, and cheap raw materials that can be easily converted into derivatives with different functional groups. One of the fundamental functional-group transformations in organic chemistry is the decarboxylative halogenation of carboxylic acids mediated by a silver salt (Hunsdiecker reaction), which has been well developed since 1930s.[9] More recently, Hunsdiecker-type reactions using catalytic amounts of silver salts have also been developed.[10] Inspired by these advances and considering that the CF3S group is generally referred to as a pseudohalide, we reasoned that a Hunsdiecker-type decarboxylative trifluoromethylthiolation (Scheme 1) may be possible if the alkyl radical generated from the well-known oxidative decarboxylation could be efficiently trapped by the electrophilic trifluoromethylthiolating reagent 1, which we recently developed in our lab.[6]

Scheme 1. Proposed radical trifluoromethylthiolation.

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[ ] These authors contributed equally to this work. [**] We gratefully acknowledge financial support from the National Basic Research Program of China (2012CB821600), the Key Program of the Natural Science Foundation of China (21032006), the National Natural Science Foundation of China (21172245/2117 and 2244/21372247), and SIOC. We thank Prof. Chaozhong Li for insightful discussions. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201402573.

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Angew. Chem. Int. Ed. 2014, 53, 1 – 6

One challenge associated with this approach is the possible oxidation of the product alkyltrifluoromethylthioether by the oxidant that is used to reoxidize the silver(I) salt. To facilitate the formation of the alkyltrifluoromethylthioether and minimize the side reaction, we used a biphasic system that could physically separate the alkyltrifluoromethylthioether from the oxidant, as inspired by the emulsion

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. Angewandte Communications radical polymerization process.[11] We herein report the use of an aqueous emulsion, which was formed by the addition of sodium dodecyl sulfate (SDS) in water and dramatically accelerated a silver-catalyzed decarboxylative trifluoromethylthiolation of secondary and tertiary alkyl carboxylic acids under mild conditions. Radical-clock and radical-cyclization experiments suggested that the reaction proceeded through a free-radical process. In order to test if the alkyl radical could be trapped by reagent 1, we initially studied the conversion of 1-adamantane carboxylic acid to trifluoromethylthiolated adamantine using reagent 1 in the presence of catalytic amounts of different silver salts (20 mol %) and 1.0 equivalent of K2S2O8 as the oxidant in different solvents.[12] As expected, the desired product was obtained in less than 12 % yield when silver salts such as AgNO3, AgOTf, AgBF4, or AgOAc were used in different solvents, such as THF, CH3CN, DMF, CH2Cl2, and acetone, at room temperature or at 50 8C (results not shown in the table). Furthermore, no significant improvement was observed when the reaction was conducted in a solvent mixture such as CH3CN/H2O (1/1; Table 1, entry 2), acetone/ H2O (1/1), or THF/H2O (1/1). In contrast, the reaction generated the desired product in 60 % yield when it was conducted in the presence of 1.0 equivalent of sodium dodecyl sulfate (SDS) in CH3CN/H2O (1/1; Table 1, entry 4). Decreasing the amount of SDS to 0.2 equivalent led to a higher yield (84 %; Table 1, entry 5). Reactions in the

Table 1: Optimization of reaction conditions for silver-catalyzed decarboxylative trifluoromethylthiolation.[a]

Entry

AgX

Additive

Solvent

Yield [%][a]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgNO3 AgSbF6 AgOTf AgOAc –

– – – nC12H25SO3Na[c] nC12H25SO3Na nC12H25SO3Na nC12H25SO3Na nC12H25SO3Na nC12H25SO3Na nC12H25SO3Na nC12H25SO3Na[f ] CH3SO3Na 4-(nC12H25)C6H4SO3Na nBu4NHSO4 nC12H25SO3Na nC12H25SO3Na nC12H25SO3Na nC12H25SO3Na

CH3CN CH3CN/H2O H2O CH3CN/H2O CH3CN/H2O CH3CN/H2O[d] acetone/H2O DMF/H2O CH2Cl2/H2O H2O H2O H2O H2O H2O H2O H2O H2O H2O

11 12

Silver-catalyzed decarboxylative trifluoromethylthiolation of aliphatic carboxylic acids in aqueous emulsion.

A silver-catalyzed decarboxylative trifluoromethylthiolation of secondary and tertiary carboxylic acids under mild conditions tolerates a wide range o...
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